The use of biodegradable materials for controlled delivery of biologically active agents has become more important in recent years. The biodegradable material can be e.g. silica sol-gel.
The sol-gel technology is based on hydrolyzation of metal-alkoxide (silane) and subsequent polymerization of metal hydroxides where three reaction steps can be identified. The three reaction steps are:
1. HydrolysisSi—OR+H2O→Si—OH+ROH2. Condensation of AlcoholSi—OR+HO—Si→Si—O—Si+ROH3. Condensation of WaterSi—OH+HO—Si→Si—O—Si+H2O
These reactions can be modified by using different Si—OR reagents, for example tetraethoxysilane (TEOS) or tetramethoxysilane can be used. Also the silane-water ratio can be modified, and water can partly be replaced with a suitable alcohol (methanol in methoxygel and ethanol in ethoxygel). Different additives, such as polyethyleneglycol, may also be used to introduce novel properties into the material. In all cases, the reaction is carried out by using acid or base as catalyst. By using a catalyst, it is possible to prepare sol-gel without any resembling alcohol, for example ethanol addition is not necessary in gels prepared from TEOS.
Silica sol-gel technology is economical and easy to use. Silica products are usually biocompatible and non-toxic. It has been shown that chemical and physical changes of silica xerogel have an effect on the releasing behavior of biologically active agents embedded in the gel. The sol-gel technique thus offers versatile possibilities for incorporation and controlled delivery of biologically active agents. These biologically active molecules can according to prior art (WO 9745367, Ahola et al, 1997; FI 19991806, Ahola et al 1999) be for example proteins (growth factors), hormones, nucleic acids (RNA, DNA) or polysaccharides. Also parts from virus capsids or whole viruses can be used, particularly for vaccination. Toremifene citrate, Selegiline hydrochloride, (−)-4-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride, ibuprofen, caffeine, peptides (levodopa), proteins (a dental enamel matrix derivative) and heparin have been used.
Silica xerogel has been made e.g. by using water, alkoxide and methanol at a temperature of 0° C. by adjusting the pH to a value between 1 and 4.5, preferably to a value between about 1.5 and 3.0, adding a biologically active molecule and allowing the mixture to gel and age at temperatures from about 0° C. up to about +40° C. and then drying the aged gel at temperatures from about +15° C. up to about +40° C. (U.S. Pat. No. 5,817,327, Ducheneye et al. 1998).
A method has been described where active molecules are entrapped in a porous, transparent glass, which has been formed using sol-gel process. The aim of this process was to make transparent glasses that are not biologically degradable so that the reactions of biologically active materials occur inside the gel and nothing is released. For this purpose a metal alkoxide is mixed with water resembling alcohol and exposed to ultrasonic energy. The single-phase solution is then mixed with an active biological material and the resultant gel is aged and dried. The active biological material is then trapped in a monolith of the gel. (WO 9304196)
In gene therapy, genes are usually administered to patients by using injections. Possible gene transfer vectors are plasmids, naked DNA or viral vectors, such as adenoviruses, adeno associated virus or retroviruses. In some application, it may be advantageous also to have a carrier, so that targeting into the desired tissue can take place without the need to use an excess of vector and/or prolong the local effect of the vector.